A nationwide survey of non-IgE-mediated gastrointestinal food allergies in neonates and infants.

BACKGROUND: Non-IgE-mediated gastrointestinal food allergies (non-IgE-GIFAs) seem to be increasing rapidly worldwide. However, nationwide studies have been limited to food-protein-induced enterocolitis (FPIES) and food-protein-induced allergic proctocolitis (FPIAP), with little attention to other non-IgE-GIFA subgroups. The aim of this study was to elucidate the clinical features of all patients with non-IgE-GIFAs, not just certain subgroups. METHODS: We conducted a nationwide cross-sectional survey of non-IgE-GIFAs in Japan from April 2015 through March 2016. A questionnaire was sent to hospitals and clinics throughout Japan. The questionnaire asked about the number of physician-diagnosed non-IgE-GIFA patients, the status of fulfillment of the diagnostic criteria, tentative classification into 4 clusters based on the initial symptoms, the day of onset after birth, complications, and the suspected offending food(s). RESULTS: The response rate to that questionnaire was 67.6% from hospitals and 47.4% from clinics. Analyses were conducted about "diagnosis-probable" patient cohort (n = 402) and the "diagnosis-confirmed" patients (n = 80). In half of the reported non-IgE-GIFA patients, onset occurred in the neonatal period. The patients were evenly distributed among 4 non-IgE-GIFA clusters. In Cluster 1, with symptoms of vomiting and bloody stool, the onset showed a median of 7 days after birth, which was the earliest among the clusters. Cow's milk was the most common causative food. CONCLUSIONS: In half of the patients, the onset of non-IgE-GIFAs was in the neonatal period. This highlights the importance of studying the pathogenesis in the fetal and neonatal periods.

Influence of household pet ownership and filaggrin loss-of-function mutations on eczema prevalence in children: A birth cohort study.

BACKGROUND: The association between pet exposure in infancy, early childhood eczema, and FLG mutations remains unclear. METHODS: This was a birth cohort study performed in Tokyo, Japan. The primary outcome was current eczema based on questionnaire responses collected repeatedly from birth to 5 years of age. Generalized estimating equations and generalized linear modeling were used to evaluate the association. RESULTS: Data from 1448 participants were used for analyses. Household dog ownership during gestation, early infancy, and 18 months of age significantly reduced the risk of current eczema. Household cat ownership also reduced the risk of current eczema, albeit without statistical significance. The combined evaluation of children from households with pets, be it cats, dogs or both, the risk of current eczema at 1-5 years of age was lower in those with household pet exposure ownership during gestation (RR = 0.59, 95 % CI 0.45-0.77) and at 6 months (RR = 0.49, 95 % CI 0.36-0.68). , Reduced risks of eczema were also observed at 2-5 (RR = 0.52, 95 % CI 0.37-0.73) and 3-5 years of age (RR = 0.50 95 % CI 0.35-0.74) when the respective household pet ownership were evaluated at 18 months and 3 years of age. These protective associations of reduced risk of eczema were only observed in children without FLG mutations. CONCLUSIONS: Household dog and pet (dog, cat, or both) ownership was protective against early childhood eczema in a birth cohort dataset. This protective association was observed only in children without FLG mutations, which should be confirmed in studies with larger cohorts.

Laundry detergents and surfactants-induced eosinophilic airway inflammation by increasing IL-33 expression and activating ILC2s.

INTRODUCTION: Epidemiological studies demonstrated that cleaning work and frequent use of cleaning products are risk factors for asthma. Laundry detergents have been reported to have epithelial barrier-opening effects. However, whether laundry detergents directly induce airway inflammation and its mechanisms in vivo remain to be elucidated. METHODS: Two commercial laundry detergents and two commonly used surfactants for cleaning and cosmetics (sodium lauryl sulfate and sodium dodecyl benzene sulfonate) were intranasally administered to mice. Lungs were analyzed using flow cytometry, histology, ELISA, and quantitative PCR. Human bronchial epithelial cells were stimulated with laundry detergents and analyzed using quantitative PCR and western blotting. Involvement of oxidative stress was assessed using an antioxidant. Dust samples from homes were analyzed to determine their detergent content by measuring their critical micelle concentration (CMC). RESULTS: The administered laundry detergents and surfactants-induced eosinophilic airway inflammation accompanied by increased IL-33 expression and activation of group 2 innate lymphoid cells (ILC2s). Detergent-induced eosinophilic airway inflammation was significantly attenuated in Rag2-/- Il2rg-/- , Il33-/- mice, and also in wild-type mice treated with NAC. Detergent-induced IL-33 expression in airways was attenuated by NAC treatment, both in vivo and in vitro. CMCs were found in all of the tested dust extracts, and they differed significantly among the homes. CONCLUSION: The laundry detergents and surfactants-induced eosinophilic airway inflammation in vivo through epithelial cell and ILC2 activation. They induced IL-33 expression in airway epithelial cells through oxidative stress. Furthermore, detergent residues were present in house dust and are presumably inhaled into the airway in daily life.

Eczema phenotypes and IgE component sensitization in adolescents: A population-based birth cohort.

BACKGROUND: Eczema patients are commonly immunoglobulin (Ig)E polysensitized. Although atopic dermatitis (AD) phenotypes have been recognized, IgE sensitization patterns based on AD phenotypes have not been well illustrated. We aimed to investigate how eczema phenotypes impact IgE component sensitization patterns. METHODS: This birth cohort study investigated a general population in the Tokyo Children's Health, Illness, and Development Study (T-Child Study) until children reached the age of 13 years. Eczema was assessed using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Allergen component specific IgE antibody titers were measured using a multiplex array ImmunoCAP ISAC. RESULTS: Persistent eczema phenotype until adolescence was strongly associated with allergic march symptoms, such as wheezing and hay fever, and oral allergy symptoms, and IgE component sensitizations of airborne (Japanese cedar, house dust mite, Timothy, cat, and dog) and cross-reactive allergens (Bet v 1 family) compared to early-remission and late-onset eczema. On the other hand, late-onset eczema did not show any strong associations with allergic symptoms and IgE sensitization. Adolescents with persistent eczema have high comorbidity of symptoms of pollen-food allergy syndrome. CONCLUSIONS: Early-onset eczema is deeply connected with the later allergic march, and late-onset eczema differs from the phenotype of allergic march. Early-onset eczema characterizing IgE sensitization was likely to be an extrinsic type, and late-onset eczema, which was not related to IgE sensitization, was likely an intrinsic type. Pollen-Food Allergy Syndrome is one of the allergic features in allergic march.

[ANTIMICROBIAL ALLERGY ASSESSMENT DURING PREGNANCY FOR APPROPRIATE ANTIMICROBIAL USE AT DELIVERY].

BACKGROUND: Avoidance of suspect drugs based solely on a history of drug allergy is detrimental to disease outcomes. Many antimicrobial allergy labels are not usually true allergy. Some studies have demonstrated that antimicrobial allergy assessments can be safely performed on pregnant women. The purpose of this study was to examine the usefulness of antibiotic allergy assessment during pregnancy in Japan. METHODS: We reviewed pregnant women who reported antimicrobial allergies and were referred to the allergy center. Allergists conducted an interview and skin test and selected antibiotics that could be used at delivery. RESULTS: Twenty-four pregnant women were referred to as having antimicrobial allergies. Most of the suspected antimicrobials were cephalosporin (13 cases, 52%) and penicillin (9 cases, 36%). Five women were ruled out only by our interviews. Of the remaining 20 cases, 10 were immediate type, 6 were non-immediate type, and 4 were unknown. All 21 pregnant women who needed antimicrobials were able to use the first-line drugs (ß-lactam antimicrobials) at the time of delivery. No surgical site infections or allergic reactions were observed. CONCLUSION: Pregnant women with antimicrobial allergy labels could be evaluated by antimicrobial allergy assessment during pregnancy, and first-line antimicrobials were safely and properly used at delivery.

[AN ADOLESCENT CASE OF HAE-NL-C1INH (WHO WAS) MISDIAGNOSED WITH WHEAT ALLERGY AND MULTIPLE DRUG ALLERGIES].

Hereditary angioedema (HAE) is frequently misdiagnosed as drug allergy. It is essential to differentiate HAE from allergy. Diagnosing HAE-normal-C1INH (conventional HAE type III), presenting normal C1-INH, is even more difficult. Here, we report a case of a 17-year-old female diagnosed with HAE and having labeled wheat and multiple drug allergies. She had been suffering from skin edema and abdominal symptoms since childhood. After taking wheat at 13 years old, she had multiple episodes of the same symptoms. Wheat allergy was suspected, and she started eliminating wheat. Multiple attacks were observed after several drug use, and drug allergy was labeled. However, her attacks did not improve after eliminating wheat and the suspected drugs. Her C4 and C1-INH activity was normal, but we diagnosed her with HAE-normal-C1INH based on her family history, multiple attacks after dental procedures, ineffective antihistamines, and significant efficacy of C1-INH infusion. A double-blind, placebo-controlled wheat challenge test at our hospital was negative, and wheat removal was lifted. Drugs could be de-labeled by allergic tests and history. Repeated attacks of unexplained edema and abdominal pain should be differentiated from HAE and lead to an appropriate diagnosis.

[A CASE OF INDUCIBLE LARYNGEAL OBSTRUCTION UNSUCCESSFULLY TREATED AS SEVERE ASTHMA WAS WELL CONTROLLED AFTER APPROPRIATE DIAGNOSIS AND INSTRUCTION OF THERAPEUTIC BREATHING MANEUVERS].

BACKGROUND: Inducible laryngeal obstruction (ILO) refers to respiratory disorders caused by airflow limitation in the larynx, including vocal cord dysfunction, and may sometimes be misdiagnosed as bronchial asthma (BA). Here, we report the case of an 11-year-old boy diagnosed with BA in infancy. He was referred to our Allergy Center and was taking a high dose of inhaled corticosteroids (ICS) due to frequent coughing from the age of 10 years and persistent coughing following COVID-19 infection at the age of 11. However, the patient continued to experience frequent coughing attacks and repeated visits to the emergency department after inhalation of ß2-stimulants failed to improve his cough. We admitted him to the allergy center for examinations to assess the BA severity. In the airway hypersensitiveness test, saline inhalation performed prior to methacholine inhalation caused expiratory stridor and respiratory distress in the larynx, which worsened with ß2-stimulant inhalation. Based on these results, we ruled out BA and diagnosed ILO. We instructed him on breathing maneuvers, and he was able to respond appropriately when symptoms appeared. We then started reducing his ICS dose.

[JAPANESE TRANSLATION AND LINGUISTIC VALIDATION OF THE RECAP OF ATOPIC ECZEMA (RECAP)].

BACKGROUND: The Recap of atopic eczema (RECAP), a new core outcome of the atopic dermatitis trial, was translated into Japanese and linguistically validated. METHODS: Translation into Japanese was accomplished according to the ISPOR (International Society for Pharmacoeconomics and Outcome Research) guidelines and the basic guidelines for scale translation. The translation process included two forward translations, reconciliation with native English speakers, third-party back translation, cognitive debriefing, review and harmonization by the original authors. Twenty-seven atopic dermatitis and pediatric specialists from 21 centers in Japan participated in the translation process. Cognitive debriefing was conducted through face-to-face interviews using a think-aloud method with the interview guide including questions about comprehensibility, relevance, comprehensiveness, recall period and suggested improvements, based on the COSMIN methodology. RESULTS: No linguistic or cultural problems were encountered in the translation into Japanese. Cognitive debriefings were conducted with 10 adult patients and 10 parents of pediatric patients. Some minor modifications were made following discussion and approval by the research team and the original authors. The Japanese version of RECAP was considered to be understandable, comprehensive and relevant for adult patients and families of pediatric patients. CONCLUSION: The Japanese version of the RECAP, which has been validated as linguistically equivalent to the original version, is now available. Further evaluation of the measurement properties is needed in the future.

Food-Induced Anaphylaxis among Children Weighing <15 kg: A Single-Center Case Series of the Pediatric Emergency Department.

INTRODUCTION: Food-induced anaphylaxis among infants shows an increasing prevalence; however, the prescription of epinephrine auto-injectors (EAIs) for children weighing <15 kg is associated with issues of the needle length and the epinephrine dose. Several studies have shown age-related differences in food-induced anaphylaxis, although little is known about the weight-related differences in food-induced anaphylaxis. This study aimed to reveal the incidence, clinical characteristics, and management of food-induced anaphylaxis in children weighing <15 kg. METHODS: This chart review included children who visited the pediatric emergency department (ED) of the National Center for Child Health and Development (Tokyo, Japan) from January 2014 to December 2016 and were diagnosed with food-induced anaphylaxis. The severity of anaphylaxis was evaluated using the Sampson Grading Scale. RESULTS: Of 89,232 ED visits, 444 visits included patients with food-induced anaphylaxis, after excluding cases of food-induced anaphylaxis related to oral desensitization therapy. The incidence was 4.98 per 1,000 visits. More than half of the children (n = 247/444, 55.6%) weighed <15 kg. The proportion of grade 3 and higher severity anaphylactic symptoms was 74.5% (184/247) in children weighing <15 kg and 79.2% (156/197) in children weighing 15 kg or more. The recurrence rate of food-induced anaphylaxis was 22.3% (55/247) in children weighing <15 kg and 48.7% (96/197) in children weighing 15 kg or more. Among the children weighing <15 kg, the proportion of those with recurrent food-induced anaphylaxis was 4 times higher in children weighing 10-15 kg than in those weighing <10 kg (32.2% [47/146] vs. 7.9% [8/101]). The proportion of patients who were prescribed EAIs before each visit was 25.5% (14/55) in children weighing <15 kg with a history of food-induced anaphylaxis. CONCLUSION: Food-induced anaphylaxis among children weighing <15 kg occurred as frequently and was as severe as that among children weighing 15 kg or more. However, the proportion of patients prescribed EAIs was very low in children weighing <15 kg with food-induced anaphylaxis. The potential need for EAIs is suggested among children weighing <15 kg, especially among children weighing 10 kg or more but <15 kg.

[ANAPHYLACTIC REACTION TO LYSOZYME CHLORIDE-INCLUDING DEODORANT SPRAY IN A CHILD WITH EGG ALLERGY].

BACKGROUND: Lysozyme chloride is a bactericidal substance that is included as an active ingredient in many medicines and quasi-drugs. We experienced a case of anaphylactic reaction caused by deodorant spray-containing lysozyme chloride. CASE: The patient was a 10-year-old girl who had an egg allergy. She visited an emergency department because of urticaria, wheezing, dyspnea, and pallor after she used deodorant spray that contained lysozyme chloride derived from hen's egg white. Results for deodorant spray and lysozyme chloride were positive in both skin prick tests and basophil activation tests. According to the medical history and the results, her condition was diagnosed as an anaphylactic reaction to lysozyme chloride in the deodorant spray. DISCUSSION: Although ingredient labelling is obligatory for lysozyme chloride in quasi-drugs, lysozyme chloride is not often described to be derived from egg white. It is important to alert patients with egg allergy to avoid lysozyme chloride-containing products.

[ACUTE TREATMENT AND LONG-TERM PROGNOSIS OF SEVERE PROTEIN-LOSS IN ATOPIC DERMATITIS (SPLAD)].

BACKGROUND: Atopic dermatitis (AD) in early infancy can lead to severe protein-loss in atopic dermatitis (SPLAD). The aim of this study was to elucidate the prognosis of SPLAD. METHODS: This was a single-center, retrospective, observational study based on medical records. Participants comprised 61 children with SPLAD hospitalized at the Allergy Center, National Center for Child Health and Development, from 2002 to 2017. We examined patient characteristics, blood test results, and prognoses up to 3 years, including frequency of topical corticosteroid-(TCS) use and food intake status. RESULTS: All participants improved hypoproteinemia and electrolyte abnormalities with AD treatment alone, without intravenous fluids. We performed proactive therapy to maintain remission by gradually decreasing the frequency of TCS-use. After 1, 2, and 3 years, 77%, 92%, and 95%, respectively, remission was maintained by using TCS 2 days a week or less, whereas 39% did not require TCS after 3 years. No participants received systemic therapy, including systemic steroids, immunosuppressants, or biologics. We observed that 29% of infants younger than 1 year at admission had eliminated one or more egg, milk, or wheat component after 3 years. CONCLUSIONS: Even in patients with SPLAD, the most severe AD, TCS-use may be reduced to 2 days per week or less after 3 years with appropriate skin treatment.

Consensus statements on pediatric atopic dermatitis from dermatology and pediatrics practitioners in Japan: Goals of treatment and topical therapy.

BACKGROUND: Pediatric atopic dermatitis (PAD) is a pluricausal disease and is frequently seen in dermatological and pediatric practice. Therefore, it is important to find common views in clinical practice and to promote consensus among practitioners. Aiming to obtain common views among dermatologists and pediatricians and to disseminate them widely in clinical practice, we held the PAD Consensus Forums described herein. METHODS: Questionnaire surveys of treatment goals and drug therapy were conducted to prepare topics for discussion at the PAD Consensus Forums. Reaching consensus was defined as agreement among at least 70% of the participants. RESULTS: As a result of discussion among 24 dermatologists and 25 pediatricians, consensus was obtained on 7 topics. These topics configure 3 consensus of treatment goals (Attainment targets were divided into the short/medium term and the long term. Attainment targets were associated with the primary evaluation domains of the Harmonising Outcome Measures for Eczema (HOME) roadmap, etc.) and 4 consensus of drug therapy (The number of applications of topical anti-inflammatory drugs in the acute phase and selection and ideal intervals between applications of topical anti-inflammatory drugs in proactive therapy, etc.). CONCLUSIONS: The consensus is expected to help practitioners set appropriate treatment goals in clinical practice and facilitate the choice of drugs for treatment.

[A CASE OF EOSINOPHILIC GASTROENTERITIS FOUND BY PICA DURING ORAL IMMUNOTHERAPY].

Eosinophilic esophagitis has been reported as a complication of oral immunotherapy (OIT), but there are only a few reports of eosinophilic gastroenteritis (EGE) occurring after OIT. EGE causes eosinophil infiltration into the gastrointestinal (GI) tract and is characterized by various digestive symptoms. We report the case of a 6-year-old boy with EGE. He was diagnosed as having immediate-type food allergies (egg, milk and wheat) by oral food challenges at 1 year of age. OIT for each food was carried out, and the amounts of the offending foods were able to be gradually increased without causing any immediate-type allergy symptoms. However, the total IgE and specific IgE values were remarkably increased at the age of 4 years and 4 months. He first developed oral mucosa symptoms and vomiting at 4 years and 10 months of age, and they gradually worsened. Stopping eggs and milk alleviated the symptoms. Nevertheless, he still occasionally vomited. He started Pica eating disorder (sand and sponge) due to anemia from 5 years and 10 months of age and developed eosinophilia without diarrhea or bloody stool. Upper and lower GI tract endoscopic examinations found no bleeding. The GI mucosa showed eosinophil infiltration of more than 40/high-power field in the stomach and duodenum, so he was diagnosed with EGE. No eosinophils were found in the esophageal mucosa. His GI symptoms and anemia improved on a multiple-food-elimination diet. Patients undergoing OIT should be closely followed up for a long time, and those with GI symptoms should be evaluated by GI endoscopy.

Palmar hyperlinearity in early childhood atopic dermatitis is associated with filaggrin mutation and sensitization to egg.

BACKGROUND/OBJECTIVES: Palmar hyperlinearity is a typical clinical feature of Filaggrin gene (FLG) null mutations. There are reports of FLG mutations and allergic sensitization; however, reports on the relationship between palmar hyperlinearity to sensitization are limited. This study aimed to examine the association between palmar hyperlinearity and sensitization in atopic dermatitis (AD) children. METHODS: This cross-sectional, case-control study included children ˂ 6 years old with moderate-severe AD whose parents consented for mutation analysis and photographic documentation. Each child underwent genotyping to detect the eight most prevalent FLG mutations in the Japanese population: R501X, 3321delA, S1695X, Q1701X, S2554X, S2889X, S3296X, and K4022X. Clinical features and parameters including egg-specific IgE were examined, and palm photographs were evaluated by 12 trained dermatologists blinded to genotyping results. RESULTS: Of the 57 patients (age range, 2 months to 5 years; median, 22 months), 16 were heterozygotes and three were compound heterozygotes. Palmar hyperlinearity, as recognized by more than two-thirds of dermatologists, was significantly associated with FLG mutation (P = 0.002, OR = 6.98, 95% CI = 2.1-23.7), and this association was observed especially in children over 2 years. Cross-shaped crease of the thenar eminence, as known in previous reports, also demonstrated significant correlation with FLG mutation. When the children were divided according to the presence or absence of palmar hyperlinearity, the egg white-specific IgE was significantly higher in the hyperlinearity group (55.9 vs 18.3 IU/mL, P < 0.05). CONCLUSIONS: Palmar hyperlinearity indicates possible inherited barrier abnormalities of the skin in early childhood. Its identification may help to predict a more accurate prognosis, such as sensitization.